Necrotizing and crescentic rapidly progressive glomerulonephritis (RPGN) results from a number of heterogeneous disease processes and has various clinical associations. However, all of these are characterized by crescentic glomerulonephritis on renal biopsy associated with a rapid decline in kidney function often necessitating long-term renalreplacement therapy if left untreated. Cellular crescents, defined as a multilayered accumulation of proliferating cells in Bowman's space, are pathognomonic of inflammatory glomerulonephritis. There are multiple causes of crescentic glomerulonephritis each leading to the irreversible loss of podocyte quiescence, aggravated endothelial injury, further damage to the glomerular filtration barrier, interrupts capillary blood flow, leading to irreversible ischemia and glomerular obsolescence. During crescent formation in mouse models of anti-glomerular basement membrane (GBM) RPGN, podocytes assume a migratory phenotype, attaching to the parietal basement membrane with their apical membrane where they proliferate for a limited period of time (Besse-Eschmann et al., 2004; Le Hir et al., 2001; Moeller et al., 2004). Recent data have confirmed that podocytes also contribute to crescent formation in man (Bariety et al., 2006; Thorner et al., 2008). Interestingly, in certain diseases such as IgA nephropathy or lupus nephritis, a classic immune complex-mediated renal disease, some of those affected develop severe crescentic glomerular lesions whereas others do not. Thus, one may hypothesize that in some instances local homeostatic mechanisms fail to maintain a quiescent phenotype in podocytes.
Accordingly, there is a need to develop new drugs that will be suitable for preventing or treating rapidly progressive glomerulonephritis (RPGN). In this way, it has been suggested that characterization of new compounds for treatment of RPGN may be highly desirable. Direct targeting of podocyte phenotype may help the glomerulus to withstand inflammatory stress and to prevent or stop the destructive process of crescent formation.
Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a group of nuclear receptors whose endogenous ligands include free fatty acids (FFAs) and eicosanoids. However, the best known PPARγ agonists are the thiazolidinediones (TZDs) (Ahmadian et al., 2013; Heikkinen et al., 2007). When activated, the PPARγ binds to DNA in complex with the retinoid X receptor (RXR), another nuclear receptor, increasing or decreasing the transcription of a number of specific genes. Although no PPARγ expression has been reported in whole human glomeruli (http://www.proteinatlas.org/ENSG00000132170/tissue/kidney), cultured podocytes constitutively express Pparγ mRNA which decreases upon the addition of puromycin aminonucleoside (PAN) (Kanjanabuch et al., 2007). Furthermore, pioglitazone, a TZD pharmacological agonist of PPARγ, increases both Ppar-γ mRNA and activity in cultured podocytes (Kanjanabuch et al., 2007). PPARγ stimulation is also effective in preventing podocyte injury in rats following the acute administration of PAN. (Zuo et al., 2012). Although the PAN model does not closely reflect any human disease TZDs have been shown to reduce albuminuria and glomerular injury in both mouse and rat models of diabetic nephropathy (Buckingham et al., 1998; Calkin et al., 2006; Cha et al., 2007; Ma et al., 2001; Yang et al., 2006). TZDs also have antiproteinuric effects in diabetic patients (Nakamura et al., 2001; Sarafidis et al., 2010). Finally, the improvement of glomerular injury by PPARγ agonism has been associated with reduced mitochondrial injury and oxidative stress in rat models of non-diabetic glomerulosclerosis such as aging-related sclerosis (Yang et al., 2009), 5/6 nephrectomy (Ma et al., 2001) and doxorubicin-induced focal and segmental glomerulosclerosis (Liu et al., 2010).
The mechanism of renoprotection conferred by PPARγ agonism is multifactorial. Antifibrotic and anti-inflammatory effects, suppression of the renin-angiotensin system, vascular protective and anti-apoptotic effects have all been proposed (Yang et al., 2012). In fact, TZDs pleiotropic actions may be effective in various cell types such as resident glomerular cells and immune cells. To date there has been no study of the glomerular PPARγ pathway in acute, severe inflammatory glomerulonephritis. This is likely due to the major focus on suppression of those aspects of the immune system mediating injury in autoimmune vasculitis rather than those promoting tissue tolerance to injury. Accordingly, most current therapeutic approaches to RPGN target the immune system (Henique et al., 2014). The current invention aimed to evaluate the proof of principle that delayed TZD administration could treat potentially lethal experimental RPGN.
Insight into the actions of PPARγ in non-immune cells was gained with podocyte-specific PPARγ loss of function in a severe model of RPGN. As pathway analysis from glomeruli of mice with RPGN and from primary podocytes suggested a potential association between PPARγ abundance and NF-E2-related factor 2 (Nrf2) transcriptional activity, the inventors went on to assess the role of Nrf2 in experimental RPGN. In experimental RPGN, Nrf2 deficient mice were phenotypically identical to mice with podocyte-specific PPARγ deficiency. These results indicate that the Nrf2-PPARγ axis is essential for maintaining podocyte tolerance to immune injury and could be a novel target for the treatment of necrotizing and crescentic RPGN.
There is no disclosure in the art of the role of PPARγ and Nrf2-PPARγ axis in rapidly progressive glomerulonephritis (RPGN), and the use of PPARγ agonists or PPARγ expression activators in the prevention or treatment of RPGN.